The present invention relates to a process for producing 1H-3-aminopyrrolidine and derivatives thereof, more particularly optically active 1H-3-aminopyrrolidine and derivatives thereof. More specifically, the present invention relates to an improved process for producing 1H-3-aminopyrrolidine and derivatives thereof, more particularly optically active 1H-3-aminopyrrolidine and derivatives thereof, from an aspartic acid starting material, more particularly an optically active aspartic acid starting material. The present invention also relates to methods for preparing certain antibacterial and psychotropic compounds by using the 1H-3-aminopyrrolidine and derivatives thereof prepared by such a process.
Optically active 1H-3-aminopyrrolidine of the 3R or 3S configuration obtained by the invention is useful as an intermediate for various organic compounds including medicines and agricultural chemicals. In particular, the optically active compound is useful as an intermediate for antibacterial (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3S)-3-(L-prolyl-amino)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid; psychotropic (S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-(cyclopropylcarbonyl-amino)-2-methoxybenzamide; and the like.
Conventional processes for producing optically active 1H-3-aminopyrrolidine include (1) a method in which a racemate is optically resolved, (2) a method in which a prochiral starting material is used, and (3) a method in which the target compound is synthesized from an optically active starting material.
With respect to (1) above, known examples thereof include a process comprising subjecting racemic N-benzyl-3-aminopyrrolidine as a starting material to preferential crystallization using an optically active carboxylic acid such as, e.g., D- and L-tartaric acids, L-(+)-mandelic acid, or L-(xe2x88x92)-pyroglutamic acid as a resolving agent to obtain an optically active N-benzyl-3-aminopyrrolidine and then eliminating the protective group to obtain optically active 1H-3-aminopyrrolidine (see JP-A-2-218664 (the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d)) and a process in which preferential crystallization is conducted using D- and L-tartaric acid derivatives as a resolving agent to obtain optically active N-benzyl-3-aminopyrrolidine (see JP-A-9-176115). However, these processes are inefficient, for example, because: (1) the synthesis of the starting material, i.e., racemic N-benzyl-3-aminopyrrolidine, requires many steps; (2) the theoretical yield in the resolution step is 50% at the most; and (3) because many steps are necessary for the recovery and recycling of the resolving agent and the antipode.
With respect to (2) above, a process is, for example, known which comprises subjecting N-benzyl-3-pyrroline to asymmetric hydroboration to stereoselectively incorporate a hydroxyl group into the 3-position, converting the hydroxylated compound into an azide through mesylation and nucleophilic substitution, and then reducing the azide (see J. Med. Chem., vol. 31, p. 1586 (1988)). However, this process is industrially disadvantageous because the N-benzyl-3-pyrroline used as a starting material and the other reagents are expensive.
With respect to (3) above, a process is, for example, known which comprises reacting optically active 1,2,4-tris(methanesulfonyl)butane obtained from an optically active 1,2,4-trisubstituted butane with benzylamine to produce 1-benzyl-3-methanesulfonoxypyrrolidine, which has one configuration in a central part of the molecule, and then subjecting it to a substitution reaction with benzylamine to produce optically active 1-benzyl-3-benzylpyrrolidine through inversion of configuration (see C. K. Ingold, Structure and Mechanism in Organic Chemistry, 2nd ed., Comel University Press, 1969, p.519). However, this process is disadvantageous in that a technique for mass-producing the optically active 1,2,4-trisubstituted butane for use as a starting material has not been established.
On the other hand, examples of the production of optically active 1H-3-aminopyrrolidine and derivatives thereof from optically active aspartic acid include the following two processes. One known process comprises protecting the amino group of optically active aspartic acid, reducing the carboxyl groups to hydroxyl groups, protecting the hydroxyl groups to conduct cyclization, and finally eliminating the protective groups to obtain the target compound (see JP-W-7-506110, which corresponds to U.S. Pat. No. 5,177,217 (the term xe2x80x9cJP-Wxe2x80x9d as used herein means an xe2x80x9cunexamined published PCT applicationxe2x80x9d) and JP-A-8-053412). The other known process comprises adding paraformaldehyde to N-benzyloxycarbonyl-L-aspartic acid, cyclizing the acid with the aid of p-toluenesulfonic acid as a catalyst, subsequently causing the cyclized compound to add benzylamine, isolating the resultant acid amide, esterifying it with thionyl chloride and an alcohol, and then cyclizing the ester to stereoselectively produce (3S)-1-benzyl-3-benzyloxy-carbonylaminopyrrolidine-2,5-dione (see Arch. Pharm. Res., vol. 19(4), pp. 312-316 (1996)).
However, these processes are unsatisfactory for industrial production, for example, because they involve many reaction steps and it is difficult to purify or isolate the compound produced in each step.
Also known is a process for stereoselectively producing (3S)-1-benzyl-3-benzyloxycarbonylamino-pyrrolidine-2,5-dione (succinimide compound) which comprises converting N-benzyloxycarbonyl-L-aspartic acid into its anhydride, causing the anhydride to add benzylamine, isolating the resultant acid amide, and cyclizing it with acetic anhydride (see JP-A-1-110626, which corresponds to EP 0 302 372). However, an investigation made by the present inventors revealed that racemization occurs in the step of succinimide synthesis in this process (see, Comparative Example 1 below). Furthermore, this process cannot be regarded as industrially advantageous because lithium aluminum hydride, which is used in the subsequent step of reducing the succinimide compound (Comparative Example 2), is expensive.
Accordingly it is one object of the invention to provide a novel process for producing 1H-3-aminopyrrolidine and derivatives thereof.
It is another object of the present invention to provide a novel process for producing optically active 1H-3-aminopyrrolidine and derivatives thereof.
It is another object of the present invention to provide a novel process for producing 1H-3-aminopyrrolidine and derivatives thereof from an aspartic acid starting material.
It is another object of the present invention to provide a novel process for producing optically active 1H-3-aminopyrrolidine and derivatives thereof from an optically active aspartic acid starting material.
It is another object of the present invention to provide an industrially advantageous process for safely producing high-quality optically active 1H-3-aminopyrrolidine and derivatives thereof at low cost from optically active aspartic acid.
It is another object of the present invention to provide a novel process for preparing 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compounds (succinimide compounds), which are useful as intermediates in such a process.
It is another object of the present invention to provide novel processes for preparing certain antimicrobial drugs by using the 1H-3-aminopyrrolidine and derivatives thereof prepared by such a process.
It is another object of the present invention to provide novel processes for preparing certain psychotic by using the 1H-3-aminopyrrolidine and derivatives thereof prepared by such a process.
These and other objects which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound (succinimide compound) can be produced, while avoiding a decrease in optical purity, by reacting an optically active amino-protected aspartic anhydride with a primary amine in an organic solvent and then subjecting the reaction product to cyclodehydration in the presence of an acid catalyst. The present inventors have further found that when the succinimide compound obtained is subjected to elimination of the protective group therefrom and then reduced with a reducing agent prepared by adding dimethyl sulfate or aluminum chloride to sodium boron hydride, then a 3-aminopyrrolidine compound having a high chemical purity and a high optical purity can be obtained. The inventors have furthermore found that either an optically active 1H-3-aminopyrrolidine compound retaining the configuration at the 3-position of the pyrrolidine ring or a salt thereof with a protonic acid can be produced in high yield by subjecting the 3-aminopyrrolidine compound or a protonic acid salt thereof to hydrogenolysis. The invention has been achieved based on these findings.
Thus, in a first embodiment, the present invention provides:
1. A process for producing 1H-3-aminopyrrolidine or a protonic acid salt thereof, which comprises:
(a) reacting an amino-protected aspartic anhydride of formula (1): 
wherein R represents a benzyloxycarbonyl group which may have one or more substituents on the benzene ring,
with a primary amine represented by the formula Rxe2x80x2NH2 wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring, to obtain a reaction product;
(b) subjecting said reaction product to cyclodehydration to obtain a 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound of formula (2): 
wherein R has the same meaning as in formula (1) and Rxe2x80x2 is as defined above;
(c) replacing R with a hydrogen at the 3-position amino group of the compound of formula (2) to obtain a 1-aralkyl-3-aminopyrrolidine-2,5-dione compound of formula (3): 
wherein Rxe2x80x2 has the same meaning as in formula (2);
(d) reducing the carbonyl groups of the compound of formula (3) to obtain either a 1-aralkyl-3-aminopyrrolidine compound of formula (4): 
wherein Rxe2x80x2 has the same meaning as in formula (2), or a salt thereof with a protonic acid; and
(e) subjecting said compound of formula (4) or said salt thereof to hydrogenolysis to obtain 1H-3-aminopyrrolidine or a protonic acid salt thereof.
In a second embodiment, the present invention provides:
2. A process for producing optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof, which comprises:
(a) reacting an optically active amino-protected aspartic anhydride of formula (1xe2x80x2) or (1xe2x80x3): 
wherein R represents a benzyloxycarbonyl group which may have one or more substituents on the benzene ring,
with a primary amine represented by the formula Rxe2x80x2NH2 wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring, to obtain a reaction product;
(b) subjecting said reaction product to cyclodehydration to obtain an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound of formula (2xe2x80x2) or (2xe2x80x3): 
wherein R has the same meaning as in formula (1xe2x80x2) or (1xe2x80x3) and Rxe2x80x2 is as defined above;
(c) replacing R with a hydrogen at the 3-position amino group of the compound of formula (2xe2x80x2) or (2xe2x80x3) to obtain an optically active 1-aralkyl-3-aminopyrrolidine-2,5-dione compound of following formula (3xe2x80x2) or (3xe2x80x3): 
wherein Rxe2x80x2 has the same meaning as in formula (2xe2x80x2) or (2xe2x80x3);
(d) reducing said compound represented by formula (3xe2x80x2) or (3xe2x80x3) to obtain either an optically active 1-aralkyl-3-aminopyrrolidine compound of formula (4xe2x80x2) or (4xe2x80x3): 
wherein Rxe2x80x2 has the same meaning as in formula (2xe2x80x2) or (2xe2x80x3), or a salt thereof with a protonic acid; and
(e) subjecting the compound of formula (4xe2x80x2) or (4xe2x80x3) or said salt thereof to hydrogenolysis to obtain optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof.
In a third embodiment, the present invention provides:
3. A process for producing optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof, which comprises:
(a) a step for obtaining a reaction product of an optically active amino-protected aspartic anhydride of formula (1xe2x80x2) or (1xe2x80x3): 
wherein R represents a benzyloxycarbonyl group which may have one or more substituents on the benzene ring,
with a primary amine represented by the formula Rxe2x80x2NH2 wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring;
(b) a step for converting said reaction product to an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound of formula (2xe2x80x2) or (2xe2x80x3): 
wherein R has the same meaning as in formula (1xe2x80x2) or (1xe2x80x3) and Rxe2x80x2 is as defined above;
(c) a step for converting the compound represented by formula (2xe2x80x2) or (2xe2x80x3) to an optically active 1-aralkyl-3-aminopyrrolidine-2,5-dione compound of formula (3xe2x80x2) or (3xe2x80x3): 
wherein Rxe2x80x2 has the same meaning as in formula (2xe2x80x2) or (2xe2x80x3);
(d) a step for converting the compound of formula (3xe2x80x2) or (3xe2x80x3) to either an optically active 1-aralkyl-3-aminopyrrolidine compound of formula (4xe2x80x2) or (4xe2x80x3): 
wherein Rxe2x80x2 has the same meaning as in formula (2xe2x80x2) or (2xe2x80x3),
or a salt thereof with a protonic acid; and
(e) a step for converting the compound of formula (4xe2x80x2) or (4xe2x80x3) or said salt thereof to hydrogenolysis to obtain optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof.
In a fourth embodiment, the present invention provides:
4. A process for producing an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound of formula (2xe2x80x2) or (2xe2x80x3): 
wherein R represents a benzyloxycarbonyl group which may have one or more substituents on the benzene ring; and Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring,
which process comprises:
(a) reacting an optically active amino-protected aspartic anhydride of formula (1xe2x80x2) or (1xe2x80x3): 
with a primary amine of the formula Rxe2x80x2NH2 wherein R and Rxe2x80x2 are as defined above, to obtain a reaction product; and
(b) subjecting said reaction product to cyclodehydration in the presence of an acid catalyst.
In a fifth embodiment, the present invention provides:
5. A process for producing an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound of formula (2xe2x80x2) or (2xe2x80x3): 
wherein R represents a benzyloxycarbonyl group which may have one or more substituents on the benzene ring; and Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring,
which process comprises:
(a) dehydrating an optically active amino-protected aspartic acid of formula (B) or (Bxe2x80x2): 
wherein R has the same meaning as in formula (2xe2x80x2) or (2xe2x80x3), to obtain an optically active amino-protected aspartic anhydride;
(b) reacting said anhydride with a primary amine of the formula Rxe2x80x2NH2 wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring, to obtain a reaction product; and
(c) subjecting said reaction product to cyclodehydration, wherein said reacting said anhydride and said subjecting said reaction product are carried out in a same reactor without removing said reaction product from said reactor between said reacting said anhydride and said subjecting said reaction product.
In a sixth embodiment, the present invention provides:
6. A process for producing optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof, which process comprises:
(a) subjecting a compound of formula (4xe2x80x2) or (4xe2x80x3): 
wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring, or a salt thereof with a protonic acid, to hydrogenolysis to obtain said optically active 1H-3-aminopyrrolidine or a protonic acid salt thereof.
In a seventh embodiment, the present invention provides:
7. A process for producing an optically active 1-aralkyl-3-aminopyrrolidine compound of formula (4xe2x80x2) or (4xe2x80x3): 
wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring, or a salt thereof with a protonic acid,
which process comprises:
(a) reducing an optically active l-aralkyl-3-aminopyrrolidine-2,5-dione compound of formula (3xe2x80x2) or (3xe2x80x3): 
wherein Rxe2x80x2 has the same meaning as in formula (4);
with a reducing agent prepared by adding dimethyl sulfate or aluminum chloride to sodium boron hydride.
In a eighth embodiment, the present invention provides:
8. A process for producing a 1-methyl-carbapenem derivative represented by the following formula (I): 
wherein R21 represents a hydrogen or methyl group; R22 represents hydrogen or an ester residue which is hydrolyzable in vivo; R27 represents hydrogen, methyl or ethyl; B represents 1,4-diphenylene, 1,4-cyclohexylenemethyl, methylene, methyl ethylene, ethylene, trimethylene, or 2-hydroxypropylene; R28 represents formimidoyl, acetoimidoyl, or amidino; or the group xe2x80x94Bxe2x80x94NR27R28 represents a 5 or 6 membered cyclic group,
which process comprises converting 1H-3-aminopyrrolidine or a protonic acid salt thereof to said compound of formula (I),
the improvement being said 1H-3-aminopyrrolidine or a protonic acid salt thereof is produced by the present process.
In a ninth embodiment, the present invention provides:
9. A process for producing a N-(3-pyrolidynyl) benzamido derivative represented by the following formula (II): 
wherein R11 represents a halogen atom; R12 represents an alkoxy group having from 1 to 3 carbon atoms; R14 represents a hydrocarbon ring group having from 3 to 6 carbon atoms which may be unsubstituted or substituted by halogen atom,
which comprises converting a compound of formula (4xe2x80x2) or (4xe2x80x3)or protonic acid salt thereof to said compound of formula (II),
the improvement being said compound of formula (4xe2x80x2) or (4xe2x80x3) or protonic acid salt thereof is produced by the present process.
In a tenth embodiment, the present invention provides:
10. A method for producing a compound of formula (III): 
wherein X is hydrogen or a carboxy protecting group and pharmaceutically acceptable salts thereof, which comprises converting the compound of formula (4xe2x80x2) or (4xe2x80x3) produced by the present invention to said compound of formula (III).
Thus, according to the present invention, a high-quality optically active 1H-3-aminopyrrolidine compound can be industrially advantageously produced safely at low cost from an optically active aspartic acid.
In the process of the present invention, aspartic acid is used as the starting material. In the detailed description which follows, the present methods will be discussed in the context of the use of an optically active aspartic acid as the starting material for the production of optically active 1H-3-aminopyrrolidine and derivatives thereof. However, it is to be understood that the present methods may be likewise carried out starting with aspartic acid which is not optically active or is not a single pure enantiomer. In fact, although the following detailed description describes the use of a staring material obtained from L-aspartic acid, it should be recognized that the present processes could instead use D-aspartic acid as the starting material. It should also be understood that the degree of optical activity exhibited by the 1H-3-aminopyrrolidine compounds produced from the present process will depend to some extent on the degree of optical activity exhibited by the aspartic acid used as the starting material. However, it is preferred that the 1H-3-aminopyrrolidine and derivatives thereof produced by the present process exhibit an optical activity which is at least 50% ee, preferably at least 75% ee, more preferably at least 90% ee, even more preferably at least 95%, even more preferably at least 99% ee, where the term xe2x80x9ceexe2x80x9d refers to the enantiomeric excess of the product. It is also especially preferred that the asymmetirc carbon atom at the 3 position of the pyrrolidine ring in the 1H-3-aminopyrrolidine and derivatives thereof produced by the present process have the same absolute configuartion as the alpha carbon in L-aspartic acid.
In the context of the present invention, it is to be understood that the formula (4): 
indicates that the stereochemistry at the 3-position of the pyrrolidine ring is unspecified. That is, formula (4) encompasses all compounds of that formula regardless of the stereochemistry at the 3-position of the pyrrolidine ring and includes the racemate, the pure L enantiomer, the pure D enantiomer, and all degrees of enantiomeric excess between the racemic mixture and either the L enantiomer or the D enantiomer.
It should also to be understood that the formula (4xe2x80x2): 
indicates that the stereochemistry at the 3-position of the pyrrolidine ring is of the configuration. That is, formula (4xe2x80x2) encompasses not only the pure S-enantiomer, but also all compounds of that formula so long as there is an enantiomeric excess of the shown enantiomer.
It should also to be understood that the formula (4xe2x80x3): 
indicates that the stereochemistry at the 3-position of the pyrrolidine ring is of the R configuration. That is, formula (4xe2x80x3) encompasses not only the pure R-enatiomer, bit also all compounds of that formula so long as there is an enantiomeric excess of the shown enantiomer.
The present processes will now be described in detail in the context of using optically active aspartic acid as a starting material to produce optically active 1H-3-aminopyrrolidine and derivatives thereof. The steps of the process of the invention are shown in the following scheme I. 
Production of Optically Active Amino-protected Aspartic Acid (Step A)
The optically active amino-protected aspartic acid to be used may be a commercially available one, or may be synthesized from an optically active aspartic acid. For example, (3S)-N-benzyloxycarbonylaminoaspartic acid can be produced by reacting a commercial product of optically active aspartic acid with benzyloxycarbonyl chloride in the presence of a base (see, for example, JP-A-64-63565, JP-A-60-190754, JP-A-60-185755, JP-A-60-136550, JP-A-57-14570, and JP-A-56-110661, all of which are incorporated herein by reference in their entirety). In formula (B), R has the same meaning as in formula (1), and the remaining compounds of formula (B) may also be prepared by appropriate variation of the reagents and conditions described in JP-A-64-63565, JP-A-60-190754, JP-A-60-185755, JP-A-60-136550, JP-A-57-14570, and JP-A-56-110661.
Production of Optically Active 3-(Protected Amino)pyrrolidine-2,5-dione Compound (Step B and Step 1)
The optically active amino-protected aspartic acid (B) is subjected to a dehydration reaction to thereby obtain an optically active amino-protected aspartic anhydride represented by the following formula (1): 
wherein R represents a benzyloxycarbonyl group which many have one or more substituents on the benzene ring. Specifically, this reaction is accomplished by heating the acid together with a dehydrating agent in an organic solvent or without using a solvent.
Examples of the substituents which the benzene ring may have include alkoxy groups having 1 to 3 carbon atoms, such as methoxy, ethoxy, and propoxy; halogen atoms such as fluorine, chlorine, and bromine atoms; and nitro.
Specific examples of the substituent R include benzyloxycarbonyl, 4-bromobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 3,5-dimethoxybenzyloxycarbonyl. Preferred of these are benzyloxycarbonyl and 4-bromobenzyloxycarbonyl.
Examples of the organic solvent include lower-alkyl esters of lower fatty acids, such as ethyl acetate, propyl acetate, and butyl acetate, aliphatic hydrocarbons such as hexane, heptane, and octane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Preferred of these are lower-alkyl esters of lower fatty acids. More preferred is ethyl acetate.
Examples of the dehydrating agent include lower fatty acid anhydrides such as acetic anhydride and trifluoroacetic anhydride, lower fatty acid chlorides such as acetyl chloride and propionyl chloride, and halogenating agents such as thionyl chloride. More preferred are lower fatty acid chlorides.
This step will now be described in detail in the context of the production of N-benzyloxycarbonyl-L-aspartic anhydride. However, it is to be understood that the other compounds of formula (1) may be produced by variation of the conditions set forth below and that the selection of the appropriate conditions for the production of any compound of formula (1) from those set out below is within the skill of one skilled in the art.
In the case where N-benzyloxycarbonyl-L-aspartic anhydride, for example, is produced as the compound represented by formula (1), acetyl chloride is used as the dehydrating agent in an amount of generally at least 1.0 mol, preferably at least 1.2 mol, per mol of the (3S)-N-benzyloxycarbonylaminoaspartic acid. The reaction is conducted at a temperature of generally from 10 to 100xc2x0 C., preferably from 30 to 60xc2x0 C. Although the reaction time varies depending on the temperature, the reaction substantially terminates usually in 1 to 5 hours. It is preferred to conduct the reaction with stirring in an inert gas stream, e.g., nitrogen, in order to remove the hydrogen chloride being yielded. After completion of the reaction, the solvent and the excess acetyl chloride are distilled off under reduced pressure. A poor solvent is added to the residue to crystallize the reaction product. As the poor solvent may be used an aromatic hydrocarbon such as toluene or xylene, or an aliphatic hydrocarbon such as hexane, heptane, or octane, or the like. The crystals formed are isolated by filtration and vacuum-dried to obtain an optically active amino-protected aspartic anhydride.
The optically active amino-protected aspartic anhydride obtained by the method described above is reacted with a primary amine represented by the formula Rxe2x80x2NH2, wherein Rxe2x80x2 represents an aralkyl group which may have one or more substituents on the aromatic ring, preferably in the presence of an organic solvent. Thereafter, the reaction product is subjected to cyclodehydration preferably in the presence of an acid catalyst. Thus, an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound is produced which is represented by the following formula (2): 
wherein R has the same meaning as in formula (1) and Rxe2x80x2 is as defined above.
Examples of the substituents which the aromatic ring of the primary amine Rxe2x80x2NH2 may have include alkoxy groups having 1 to 3 carbon atoms, such as methoxy, ethoxy, and propoxy; halogen atoms such as fluorine, chlorine, and bromine atoms; and nitro.
Specific examples of this primary amine include benzylamine, 2-bromobenzylamine, 3-bromobenzylamine, 4-bromobenzylamine, 2,4-dichlorobenzylamine, 2,6-dichlorobenzylamine, 3,4-dichlorobenzylamine, 2-nitrobenzylamine, 3-nitrobenzylamine, and 4-nitrobenzylamine. Preferred of these is benzylamine. Especially in the case where (3S)-1-benzyl-3-(carbobenzyloxyamino)pyrrolidine-2,5-dione is produced as an example of the optically active compound represented by formula (2), benzylamine is used as the primary amine.
Suitable examples of the reaction solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; aliphatic hydrocarbons such as hexane, heptane, and octane; ethers such as diisopropyl ether and dimethoxyethane; and mixed solvents comprising one or more of these. Preferred of these is toluene. It is more preferred to use a mixed solvent comprising a polar solvent, e.g., dimethylformamide, dimethylacetamide, dimethyl sulfoxide, or a polyethylene glycol dialkyl ether, and toluene. The proportion of the polar solvent is generally from 1 to 20% by volume, preferably from 5 to 10% by volume, based on the toluene.
Examples of the acid catalyst include protonic acids such as sulfuric acid, phosphoric acid, and p-toluenesulfonic acid; and Lewis acids such as aluminum chloride and zinc chloride. Preferred of these is p-toluenesulfonic acid. The acid catalyst is used in an amount of generally from 0.1 to 50% by mole, preferably from 1 to 20% by mole, based on the moles of (N-carbobenzyloxy)aspartic anhydride.
From the standpoint of preventing the optical purity from decreasing, the reaction temperature is generally from 60 to 150xc2x0 C., preferably from 80 to 120xc2x0 C., although it varies depending on the boiling point of the solvent used. It is preferable that the water being created by the dehydration be continuously discharged from the system by azeotropy.
After completion of the reaction, the solvent is removed by distillation, and a solvent in which the reaction product is readily soluble, such as, e.g., an acetic acid ester, is added to the residue. This solution is washed successively with an aqueous acid solution and an aqueous alkali solution. Finally, the solvent is removed by distillation. Thus, a compound represented by formula (2) having a high optical purity and a high chemical purity is obtained. In particular, an example of this optically active compound is (3S)-1-benzyl-3-(carbobenzyloxyamino)pyrrolidine-2,5-dione.
In the case where an organic solvent comprising an aromatic hydrocarbon was used as the reaction solvent, purification by crystallization after completion of the reaction can be conducted without the necessity of solvent removal by distillation. Specifically, the purification can be conducted in the following manner. After completion of the reaction, the reaction mixture is washed with an aqueous alkali solution and then with a saturated aqueous sodium chloride solution while being kept at 70xc2x0 C. or higher, subsequently heated and refluxed to conduct azeotropic dehydration, and then cooled to cause crystallization. Crystals begin to precipitate at around 65xc2x0 C., and this mixture is further stirred at 20xc2x0 C. Thus, optically active (3 S)-1-benzyl-3-benzyloxycarbonyl-aminopyrrolidine-2,5-dione purified to a higher optical purity can be obtained.
Toluene is preferred as the aromatic hydrocarbon. A mixed solvent comprising an aromatic hydrocarbon and an aliphatic hydrocarbon such as hexane, heptane, or octane may be used.
It is also possible to use a technique in which after an optically active amino-protected aspartic anhydride is synthesized from an optically active amino-protected aspartic acid, an optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound is synthesized from the anhydride in the same reactor without removing the anhydride from the reactor. Specifically, this method comprises synthesizing an optically active amino-protected aspartic anhydride in the same manner as described above, subsequently replacing the reaction solvent, and subjecting the acid anhydride to reaction with a primary amine Rxe2x80x2NH2 and then to cyclodehydration according to the method described above. Thus, the target optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound can be synthesized.
From the optically active 3-(protected amino)pyrrolidine-2,5-dione compound represented by formula (2) can be produced a compound useful as an intermediate for various organic compounds including medicines and agricultural chemicals.
Production of Optically Active 1-Aralkyl-3-aminopyrrolidine-2,5-dione (Step 2)
An optically active 1-aralkyl-3-aminopyrrolidine-2,5-dione compound represented by the following formula (3): 
wherein Rxe2x80x2 has the same meaning as in formula (2), can be produced by eliminating the protective group from the 3-position amino group of the optically active 1-aralkyl-3-(protected amino)pyrrolidine-2,5-dione compound.
Specifically, the compound represented by formula (2) is catalytically reduced in a hydrogen atmosphere using a metallic catalyst, e.g., Pd/C, to eliminate the protective group from the 3-position amino group to obtain the target compound. This step will now be described in detail in the context of the production (3S)-3-amino-1-benzylpyrrolidine-2,5-dione. However, it is to be understood that the other compounds of formula (3) may be produced by variation of the conditions set forth below and that the selection of the appropriate conditions for the production of any compound of formula (3) from those set out below is within the skill of one skilled in the art.
In the case where (3S)-3-amino-1-benzylpyrrolidine-2,5-dione is produced, the reaction is conducted in a solvent such as, e.g., water, methanol, ethanol, isopropyl alcohol, or 1,2-dimethoxyethane using 5% or 10% Pd/C as a catalyst in an amount of from 0.1 to 1.0% by mole, preferably from 0.2 to 0.5% by mole, based on the moles of (3S)-1-benzyl-3-benzyloxycarbonylaminopyrrolidine-2,5-dione. This reaction proceeds at a temperature of from 20 to 150xc2x0 C. and a pressure of from ordinary pressure to 30 kg/cm2. A preferred range of the pressure is from ordinary pressure to 5 kg/cm2. Usually, the reaction is completed in 2 to 30 hours.
In the case where 1,2-dimethoxyethane is to be used as a solvent in the subsequent step, use of 1,2-dimethoxyethane as a solvent in this reaction for protective-group elimination is advantageous in that the reaction mixture obtained through this reaction can be subjected to the subsequent step without isolating the reaction product and that the only act necessary therefor is to remove the catalyst by filtration.
Method 1 for Producing Optically Active 1-Aralkyl-3-aminopyrrolidine Compound (Step 3)
An optically active 1-aralkyl-3-aminopyrrolidine compound represented by the following formula (4): 
wherein Rxe2x80x2 has the same meaning as in formula (2), can be produced by reducing the carbonyl groups of the optically active 1-aralkyl-3-aminopyrrolidine-2,5-dione compound.
Specifically, a reducing agent prepared by adding dimethyl sulfate to sodium boron hydride is used for the reduction.
In the case where optically active (3S)-3-amino-1-benzylpyrrolidine is produced, the amount of sodium boron hydride to be used is generally from 1 to 7 mol, preferably from 4 to 7 mol, per mol of the optically active (3S)-3-amino-1-benzylpyrrolidine-2,5-dione used as a substrate. Dimethyl sulfate is used in the same molar amount as the sodium boron hydride.
The reduction is conducted in an inert organic solvent. Examples of the inert organic solvent include open chain ethers such as diethyl ether, methyl t-butyl ether, di-n-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether; cyclic ethers such as tetrahydrofuran and dioxane; hydrocarbons such as toluene, xylene, and tetralin; and mixed solvents composed of two or more thereof. It is preferred to use a cyclic ether, especially tetrahydrofuran.
Dimethyl sulfate is added dropwise to a tetrahydrofuran solution of sodium boron hydride at xe2x88x9210 to 10xc2x0 C., and this mixture is stirred at a temperature of from 0 to 20xc2x0 C. for from 5 to 10 hours. Subsequently, a tetrahydrofuran solution of the substrate is added thereto at xe2x88x9210 to 10xc2x0 C. and the reaction mixture is stirred. The reaction temperature is generally from 0 to 100xc2x0 C. preferably from room temperature to 50xc2x0 C. Although the reaction is conducted until substantially all the substrate disappears, the time required therefor varies depending on the reaction temperature. For example, the reaction is completed in 10 hours at 25xc2x0 C. and in 6 hours at 50xc2x0 C. By keeping the reaction temperature at 30xc2x0 C., or lower during the reduction, optical purity can be inhibited from decreasing. After completion of the reaction, water or methanol is added to the reaction mixture to decompose the excess reducing agent. The reaction mixture is concentrated, subsequently acidified with hydrochloric acid or the like, and then stirred for several hours. Thereafter, the aqueous layer is alkalified with caustic soda or the like and then extracted with an organic solvent. Thus, optically active (3S)-3-amino-1-benzylpyrrolidine having a high optical purity and a high chemical purity can be obtained.
Method 2 for Producing Optically Active 1-Aralkyl-3-aminopyrrolidine Compound (Step 3)
An optically active 1-aralkyl-3-aminopyrrolidine compound can be produced also by a method in which a reducing agent prepared by adding aluminum chloride to sodium boron hydride is used. In this method, the amount of sodium boron hydride to be used can be reduced as compared with the case of using a reducing agent prepared by adding dimethyl sulfate.
In the case where optically active (3 S)-3-amino-1-benzylpyrrolidine is produced, the amount of sodium boron hydride to be used is generally from 1 to 7 mol, preferably from 2 to 5 mol, per mol of the optically active (3S)-3-amino-1-benzylpyrrolidine-2,5-dione used as a substrate. Aluminum chloride is used in an amount of generally from 0.1 to 1 mol, preferably 0.33 mol, per mol of the sodium boron hydride.
The reduction is conducted in an inert organic solvent. Examples of the inert organic solvent include open chain ethers such as diethyl ether, methyl t-butyl ether, di-n-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, and diethylene glycol diethyl ether; cyclic ethers such as tetrahydrofuran and dioxane; hydrocarbons such as toluene, xylene, and tetralin; and mixed solvents composed of two or more thereof. It is preferred to use an open chain ether, especially 1,2-dimethoxyethane.
Aluminum chloride is added dropwise to a 1,2-dimethoxyethane solution of sodium boron hydride at 0 to 10xc2x0 C., and this mixture is stirred at a temperature of from 0 to 50xc2x0 C. for from 1 to 5 hours. Subsequently, a dimethoxyethane solution of the substrate is added thereto at 0 to 10xc2x0 C. and the reaction mixture is stirred. The reaction temperature is generally from 0 to 100xc2x0 C., preferably from room temperature to 50xc2x0 C. Although the reaction is conducted until substantially all the substrate disappears, the time required therefor varies depending on the reaction temperature. For example, the reaction is completed in 12 hours at 25xc2x0 C. By keeping the reaction temperature at 30xc2x0 C. or lower during the reduction, optical purity can be inhibited from decreasing. After completion of the reaction, water or methanol is added to the reaction mixture to decompose the excess reducing agent. The reaction mixture is concentrated, subsequently acidified with hydrochloric acid or the like, and then stirred for several hours. Thereafter, the aqueous layer is alkalified with caustic soda or the like and then extracted with an organic solvent. Thus, optically active (3S)-3-amino-1-benzylpyrrolidine having a high optical purity and a high chemical purity can be obtained.
Production of Optically Active 1H-3-Aminopyrrolidine Compound (Step 4)
An optically active 1H-3-aminopyrrolidine compound or a salt thereof with a protonic acid can be produced by subjecting the optically active 1-aralkyl-3-amino-pyrrolidine compound or a salt thereof to hydrogenolysis. Specifically, the compound represented by formula (4) or a salt thereof is catalytically reduced in a hydrogen atmosphere using a metallic catalyst, e.g., Pd/C, to eliminate the 1-position protective group and thereby obtain the target compound.
For example, in the case where (3S)-1H-3-aminopyrrolidine dihydrochloride is produced, solvents such as water, methanol, ethanol, and isopropyl alcohol are used alone or as a mixture of two or more thereof in an autoclave to conduct the reaction preferably in the pressure of an acid such as acetic acid or hydrochloric acid. The addition of an acid can heighten the rate of reaction. The acid is added in an amount of generally from 1.0 to 5.0 mol, preferably from 1.0 to 2.0 mol, per mol of the (3S)-3-amino-1-benzylpyrrolidine.
As the catalyst is, for example, used Pd/C in an amount of generally from 0.25 to 5.0% by mole, preferably from 1.0 to 3.0% by mole, based on the (3S)-3-amino-1-benzylpyrrolidine. This reaction proceeds at a temperature of from 20 to 150xc2x0 C. in a hydrogen atmosphere having a pressure of generally from ordinary pressure to 30 kg/cm2, preferably from ordinary pressure to 10 kg/cm2, more preferably from ordinary pressure to 5 kg/cm2. The reaction is completed usually in 2 to 30 hours. After completion of the reaction, the catalyst is removed by filtration, and hydrogen chloride or hydrochloric acid is added to the filtrate to cause crystallization. The crude crystals are taken out by filtration and then recrystallized. Thus, (3S)-1H-3-aminopyrrolidine dihydro-chloride having a high chemical purity and a high optical purity is obtained.
As noted above, the optically active aminopylrrolidine compounds produced by the present method are useful for producing 1-methyl-carbapenem derivatives represented by the following formula (I): 
wherein R21 represents a hydrogen or methyl group; R22 represents hydrogen or an ester residue which is hydrolyzable in vivo; R27 represents hydrogen, methyl or ethyl; B represents 1,4-diphenylene, 1,4-cyclohexylenemethyl, methylene, methyl ethylene, ethylene, trimethylene, or 2-hydroxypropylene; R28 represents formimidoyl, acetoimidoyl, or amidino; or the group xe2x80x94Bxe2x80x94NR27R28 represents a 5 or 6 membered cyclic group, which are useful as an antibacterial agents.
In the compounds of formula (I), suitable ester residues which are subject to hydrolysis in vivo, include acyloxyalkyl groups, such as pivaloyloxymethyl, acetoxymethyl, and 1-methylcyclohexylcarbonyloxymethyl; alkoxy carbonyloxyalkyl groups, such as 1-(isopropoxycarbonyloxy) ethyl and 1-(cyclohexylcarbonyloxy) ethyl; and 1-(2-oxo-1,3-dioxolene-4-yl) alkyl groups, which may have an alkyl or allyl group on the 5-position, such as 5-methyl-2-oxo-1,3-dioxolene-4-ylmethyl.
The 1H-3-aminopyrrolidine produced by the present processes may be converted to the compounds of formula (I) by the methods described in Japanese Patent No. 2955276, which is incorporated herein by reference in its entirety. As an example of the method of producing the above mentioned 1-methyl-carbapenem derivatives, the reaction for producing (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3S)-3-(L-pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid (14) by using an optical active amino pyrrolidine compound is described in reaction scheme II. However, it is to be understood that the remaining compounds of formula (I) may be prepared by varying the specific conditions, reagents, and starting materials set forth in scheme II. 
The optically active 1H-3-aminopyrrolidine compound (5) is reacted with a base and di-tert-butyl carbonate in t-butanol solvent to obtain a compound (6). Examples of the base include inorganic bases such as sodium hydroxide and potassium hydroxide and organic tertiary amines such as triethylamine, trimethylamine, and isopropylamine. Preferred are inorganic bases such as sodium hydroxide and potassium hydroxide. The compound (6) may be purified according to need by silica gel column chromatography, crystallization, etc. (step C).
Steps D to H can be carried out by the method described in Japanese Patent 2955276, which is incorporated herein by reference. Namely, the optically active compound (6) obtained in step (C) is subjected to condensation reaction with 1-(4-nitrobenzyloxycarbonyl)-L-proline (compound D-1) in acetonitrile solvent in the presence of N,N-carbonyldiimidazole to thereby obtain a compound (7) (step D).
Compound (7) is reacted with trifluoroacetic acid in dichloromethane solvent to thereby obtain compound (8) which is a pyrrolidine trifluoroacetate (step E).
Compound (8) and compound (9) are subjected to condensation reaction using a condensation agent (compound (F-1)) in acetonitrile solvent to thereby obtain compound (10) (step F).
Compound (10) is subjected to benzyl elimination in anisole, trifluoroacetic acid, and trifluoromethanesulfonic acid to thereby obtain compound (11) (step G).
Compound (11) and compound (12) are subjected to condensation reaction in acetonitrile solvent using diisopropylamine to thereby obtain compound (13) (step H).
In a solution in tetrahydrofuran/water, compound (13) is hydrogenated using a palladium/carbon catalyst to eliminate the protective groups from the compound (13). Thus, (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3S)-3-(L-amino)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylic acid (14) can be obtained (step J).
Furthermore, psychotropic N-3-pyorrolidinyl) benzamide derivatives represented by the following formula (II): 
wherein R11 represents a halogen atom; R12 represents an alkoxy group having from 1 to 3 carbon atoms; R14 represents a hydrocarbon ring group having from 3 to 6 carbon atoms which may be unsubstituted or substituted by halogen atom, which are useful as psychotropic agents, can be synthesized by using the optically active aminopylrrolidine compounds produced by the present method.
In the general formula (II), R11 is a halogen atom such as fluorine and chlorine; R12 is an alkoxy group having from 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and iso-propoxy; and R14 represents a hydrocarbon ring group having from 3 to 6 carbon atoms which may be unsubstituted or substituted by halogen atom such as cyclopropyl, cyclobutyl, cyclohexyl, phenyl, 2-fluorocyclopropyl, and 2,2-difluorocyclopropyl.
The above mentioned N-(3-pyorrolidinyl) benzamide derivatives can be produced from the compound of formula (4) by the method described in WO95/08533, which is incorporated herein by reference.
As an example of the method of producing the above mentioned N-(3-pyorrolidinyl) benzamide derivatives, the reaction for producing (S)-N-(1-benzyl-3-pyrolidinyl)-5-chloro-4-(cyclopropylcarbonylamino)-2-methoxybenzamido by using an optical active 3-aminoprolidine compound is described in reaction scheme III. However, it is to be understood that the remaining compounds of formula (II) may be prepared by varying the specific conditions, reagents, and starting materials set forth in scheme III. 
Steps K and L can be carried out by the method described in WO 95/08533 (AU 7665694). Namely, compound (15) is reacted with cyclopropionyl chloride in methylene chloride solvent in the presence of pyridine to thereby obtain compound (16) (step K).
Subsequently, compound (16) is condensed with the optically active 1H-3-aminopyrrolidine compound (4) using triethylamine (TEA) and ethyl chloroformate. Thus, (S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-(cyclopropyl-carbonylamino)-2-methoxybenzamide (17) can be obtained (step L).
As also noted above, the compound of formula (4) prepared by the present process are useful for preparing the compounds of formula (III): 
wherein X is hydrogen or a carboxy protecting group and pharmaceutically acceptable salts thereof, which are useful as antimicrobials. Suitable carboxy protecting groups are disclosed in U.S. Pat. Nos. 3,840,556 and 3,719,667 and EP 0 302 372, which are incorpoarated by reference herein in their entireties. Specifically, the compound of formula (4) may be converted to 3-acetomidopyrrolidine by first converting the 3-amino group of the compound of formula (4) to a 3-acetomido group by reaction of compound (4) with acetic anhydride, followed by removal of the Rxe2x80x2 protecting group by catalytic hydrongenolysis. The conversion of 3-acetomidopyrrolidine to the compounds of formula (III) may be carried out as described in EP 0 302 372, which, as noted above, is incorpoarated by reference herein in its entirety.